Pentoxifylline for Treatment of Resistant Major Depression

Pentoxifylline for Treatment of Resistant Major Depression: A Randomized, Double Blind, Placebo Controlled Trial

A growing body of evidence has highlighted the role of inflammation and phosphodiesterases (PDE)-related pathways in the pathogenesis of neuropsychiatric illnesses such as depression/mood disorders. Herein, we aimed to evaluate the therapeutic benefits of pentoxifylline (PTX) in the treatment of therapy-resistant depression (TRD) in adult patients with bipolar depression.

Study Overview

• Status: Completed
• Conditions: Resistant Major Depression
• Intervention / Treatment: Drug: Pentoxifylline; Drug: Placebo

Detailed Description

Depression, which affects an estimated 300 million people worldwide, is the main cause of mental health-related illness burden. Depression keeps people from attaining their full potential, depletes human capital, and is linked to suicide and other forms of mortality. Despite the fact that depressive disorders have a better prognosis than primary psychotic illnesses like schizophrenia, 20%-40% of patients treated with antidepressants do not respond to their initial treatment regimens, and up to 15% do not respond to multiple antidepressant regimens and modalities, such as electroconvulsive shock (ECT) therapy. Since the treatment resistance has been shown to increase the likelihood of full symptomatic recurrence, worsen the treatment course and quality of life; therefore, there is a critical need for innovative treatment techniques for patients who have failed to respond to traditional treatments. Inflammation is one factor that has gotten a lot of attention lately as an etiologic mechanism of treatment-resistant depression (TRD). Increased levels of (pro) inflammatory markers such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, and IL-6 are reported in a considerable percentage of patients with major depressive disorders with or without other comorbidities, including bipolar depression and TRD patients. Also, clinical factors connected to antidepressant response are linked to the reduction of inflammatory cytokines.

Moreover, cytokine antagonists, such as the chimeric anti-TNF-alpha antibody infliximab, has shown antidepressant efficacy. Hence, given the elevated levels of inflammatory activity in TRD patients, new treatments with anti-inflammatory effect might be an effective approach to treat these patients. Pentoxifylline (PTX) is a methylated xanthine derivative that has been used to treat peripheral vascular disease for more than two decades. PTX has anti-inflammatory and phosphodiesterase (PDE) inhibitory effects that enables it to inhibit PDEs competitively. Subsequently, it can increase cAMP levels, activate protein kinase A (PKA), inhibit ILs and TNF-α production, and reduce inflammation. Therefore, PTX-decreased inflammatory activity, may give rapid symptomatic alleviation for medically healthy individuals with TRD depression.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Iraq
  • Erbil, Iraq, 44001
    • Hawler Psychiatric Hospital and Private Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provide written, voluntary informed consent prior to study enrollment.
• Male or female between the ages of 18 to 65.
• Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-IV) criteria for bipolar I or II, currently experiencing a major depressive episode. A Mini-International Neuropsychiatric Interview (MINI) conducted by physician was used to confirm the diagnosis.
• Meets the criteria for treatment resistant depression (TRD) defined by failure to respond to of at least two treatment trials (antidepressant regimen or electroconvulsive therapy) during the current depressive episode.
• Prior to taking part in the trial, all patients were requested to be antidepressant free for 4 weeks or to be on a fixed psychotropic therapeutic regimen for at least 4 weeks.

Exclusion Criteria:

• Current psychotic symptoms or perceptual problems.
• The presence of a contraindication to PTX, such as a drug allergy or xanthine derivative allergy.
• Patients with substance dependence or abuse.
• Patients with concurrent active medical condition (congestive heart failure, abnormal electrocardiogram, malignancy, schizophrenia, neurological disease).
• Patients with inflammatory disorders and/or auto-immune conditions (rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, lupus)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pentoxifylline; Pentoxifylline (tablet): 400 mg twice a day for 12 weeks	Drug: Pentoxifylline; All participants will receive pentoxifylline 400 mg (orally ingested) twice a day for 12 weeks.; Other Names: Trental
Placebo Comparator: Control group; Placebo (tablet): twice a day for 12 weeks	Drug: Placebo; All participants will receive placebo (orally ingested) twice a day for 12 weeks.; Other Names: Sugar Pills

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hamilton Depression Rating Scale-17 (HAM-D-17) Scores	The HAM-D-17 is a 17-item scale that asks participants to rate the severity of their depression symptoms. Scoring is based on the 17-item scale. The total score ranges from 0 to 52, with higher numbers demonstrating more severe symptoms. Normal scores range from 0 to 7, mild depression ranges from 8 to 16, moderate depression ranges from 17 to 23, and scores of 24 and greater indicate severe depression. Remission is defined as HAM-D-17 total score ≤ 7 (primary outcome).	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate	The number of patients with a ≥ 50% drop in the Hamilton Depression Rating Scale-17 (HAM-D-17) total score.	12 weeks
Remission Rate	The number of patients reaching depression remission. Remission is defined as Hamilton Depression Rating Scale-17 (HAM-D-17) total score ≤ 7.	12 weeks
Serum level of CRP	Peripheral blood samples will be collected to assess changes in the serum levels of C- reactive protein (mg/dl).	12 weeks
Serum level of TNF-α	Peripheral blood samples will be collected to assess changes in the serum levels of tumor necrosis factor alpha (pg/ml).	12 weeks
Serum level of IL-6	Peripheral blood samples will be collected to assess changes in the serum levels of Interleukin-6 (pg/ml).	12 weeks

Collaborators and Investigators

• Sponsor: Hawler Medical University
• Investigators: Principal Investigator: Talar A Merzamohammad, Pharm. D, Hawler Medical University, College of Pharmacy, Department of Pharmacology and Toxicology

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2021
• Primary Completion (Actual): May 4, 2022
• Study Completion (Actual): June 4, 2022

Study Registration Dates

• First Submitted: March 25, 2022
• First Submitted That Met QC Criteria: April 6, 2022
• First Posted (Actual): April 12, 2022

Study Record Updates

• Last Update Posted (Actual): September 7, 2022
• Last Update Submitted That Met QC Criteria: September 5, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Bipolar Depression; Pentoxifylline; Resistant Major Depression
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Pentoxifylline
• Other Study ID Numbers: HMU PE-EC 24112021/391

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No